Background: The ECHELON-1 trial demonstrated improved outcomes for patients (pts) with advanced HL who received frontline A+AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine) vs ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), with 2-year mPFS rates of 82% and 77%, respectively. Here we report a post-hoc analysis of mPFS outcomes and clinical characteristics by Cycle 2 PET (PET2) status per independent review facility (IRF). Methods: Pts were randomized 1:1 to A+AVD or ABVD on Days 1 and 15 for up to six 28-day cycles. PET scans were conducted at the end of Cycle 2 and end of treatment. PET2 results guided an optional switch to alternative therapy at the treating physician’s discretion for pts with a Deauville score of 5. A switch to alternate therapy was not considered an event. The primary endpoint, mPFS, was defined as time to progression, death, or absence of a complete response with subsequent anticancer therapy, per IRF. Results: PET2 negativity rates (Deauville ≤3) were 89% (588/664 pts) in the A+AVD arm and 86% (577/670) with ABVD. Baseline characteristics were well-balanced across arms, with no significant differences in PET2– vs PET2+ pts in either arm. PET2 positivity rates (Deauville ≥4) were 7% (47/644) in the A+AVD arm and 9% (58/670) with ABVD; 5 total pts with a Deauville score of 5 switched to alternative frontline therapy. Subgroup analyses showed a favorable treatment effect for both subgroups in favor of A+AVD (Table 1), with 2-year mPFS (PET2– vs PET2+) of 85.2 vs 57.5% in the A+AVD arm, and 80.9 vs 42.0% in the ABVD arm. Outcomes for PET2+ pts were relatively poor in both arms, as previously reported. Conclusions: Overall, ECHELON-1 demonstrated a treatment effect in favor of A+AVD over ABVD. This post-hoc analysis showed a similar treatment effect on mPFS consistently in favor of A+AVD regardless of PET2 status. Clinical trial information: NCT01712490